Thursday, July 19, 2018

French MA Report translated using Google

TRANSLATED FROM FRENCH USING GOOGLE TRANSLATE.

NATIONAL COMMISSION OF VETERINARY DRUG EXPERT REPORT OF DRUG
on the CNPV NOTICE - 02 9/12/2003

Assessment of adverse effects in the short and medium term oral progestins
based megestrol acetate used for the prevention and interruption of heat in dogs and cats of 9 December 2003


I, Gerard Keck, president of the National Committee of veterinary pharmacovigilance
certify that the expert report on adverse short and medium term effects of progestin-only
oral-based megestrol acetate used for the prevention and disruption of heat in dogs and cats. and conclusions presented in this report were adopted at the meeting of the National Committee of veterinary pharmacovigilance of 9 December 2003.
Ferns, 2February 2004 GERARDKECK

_____________
INTRODUCTION
The National Commission of Veterinary Pharmacovigilance has received May 30, 2002 by AFSSA -ANMV (National Agency for Veterinary Medicinal Products) a request for an opinion on undesirable effects in short and long-term oral progestins based megestrol acetate used for the prevention and'. Interruption of heat in carnivores This request results from two complaints from cat owners and stating, after taking a veterinarian based drug megestrol acetate in appearance:
􀂃 a complicated pyometra of Acute renal failure after a single dose
􀂃 mammary tumors after several doses.

In both cases, uterine infections and breast led to the death of the animal. These complaints emphasize the lack of information on the risks involved taking this drug both
on the package leaflet and when buying from pharmacies (this product is distributed
exclusively in pharmacies).
These veterinary drugs basis of megestrol acetate for the carnivores may be
exempted from the regulation of poisonous substances if:
􀂃 these veterinary drugs are administered orally or subcutaneously presented
tablets,
􀂃 the limit dose of active ingredient per tablet (unit making) is 20 mg
􀂃 the maximum amount of substance is given to the public of 200 mg (Order of 3 December 1986 amending for pets Order of 20 July 1949 on the exemption from the
regulation of substances poisonous for veterinary medicine.)

In the double objective of assessing the risks associated with the administration of the veterinary drugs and reconsider this particular provision to exempt, AFSSA calls on the Commission to specify the frequency and risk characteristics of the use of all medicinal products veterinary containing megestrol acetate used for the prevention and disruption of heat.
4

Megestrol acetate is a synthetic progestin steroid progesterone derivative used
only by oral. Its contraceptive effect is due to inhibition at the hypothalamic level of
pulsatile GnRH secretion and thus secondarily cyclical secretion of pituitary FSH and
LH, thus inducing a prolonged anoestrus. This molecule, like other synthetic progestogens, also a non-selective affinity for progesterone receptors present in the target organs of sex steroid hormones such as the uterus and breasts: the uterus, megestrol acetate can induce hyperplasia glandulokystique variable intensity and udder it causes an increase in the local production of growth factors GH (growth hormone) and IGF 1-5 (insulin like growth factors) leading to breast enlargement. It also has a central action on the limbic system and antagonizes the effect of insulin (11). Antiandrogen Its share (11) justifies its use for hypersexualisme. This study focused on 11 veterinary drugs for which reports periodic safety were provided by the licensees of marketing. A total of 98 declarations submitted during the period 1994-2002 were studied.70 of these statements relate to reactions occurring in .cats after administration and 28 other ones occurring in dogs during this period a total of 131,937,960 tablets were sold-.
This report is structured as follows:
 -Study of side effects reported in cats
- Study of reported adverse reactions in dogs
- Bibliographic data
- Conclusion and proposals

5
1. STUDY OF SIDE EFFECTS REPORTED IN THE CAT
1.1. DRUGS BASED MEGESTROL ACETATE FOR THE PREVENTION AND INTERRUPTION OF HEAT
Eight veterinary drugs, whose characteristics are reported in Table 1 are available
in veterinary medicine for the treatment and the interruption of heat in the cat :
Table 1
Veterinary Drugs based megestrol acetate for the treatment and the interruption
of heat in the cat


   species       Brand name        dosage/pill     pills per pkg.               ?


In cats, the generally recommended for six of the seven drug regimens
Veterinary are 5 mg / animal every 15 days to prevent heat. For Pilucalm and
Pill'kan5, the regimen is different (Table 2).
For the prevention of heat (Table 2), regimens differ from one medicine.
to another veterinary  Some of these veterinary drugs Mégécat, Mégédine can also be
used to treat miliary dermatitis.
Table 2
progestin regimens based megestrol acetate available for feline species
Preventing heat, heat Interruption


Felipil -      Prev -   5 mg daily for 15 days  -                      Int – 5 mg per day for 3-5 days
Megecat    Prev     5 mg daily for 15 days                          Int  -not given
Megepil     Prev     5 mg daily for 15 days                          Int -     not given
Minipil        Prev     5 mg daily for 15 days                          Int – not given
Megedine  Prev    not given                                             Int 10 mg per day for 8 days 
Pill'ka 5 .    Prev-   2.5 mg 3 times per week for 2 months Int-5 mg for 8 days
Pilucalm     Prev -   5 mg/10 kg  for 32 days                        Int-20 mg/10 kg / 8 days





















Side effects (Table 3) differ veterinary drugs:
Table 3











Table 3 translation :


Title : Contraindications and side / adverse
Column Headings : Name  Submitted side effects    Adverse Contraindication

Felipil 
S/E - treatment sometimes results in males and females decreased vagrancy and
sometimes increased appetite.
A/C - metritis, pregnancy, diabetes, association with Estrogen

Megecat
S/E - Increased appetite, weight gain.
A/C - Diabetes, pregnancy, infection, Reproductive tract  pre-pubescent females.

Mégépil
S/E - tolerance pharmaceutical form Mégépil cat has been evaluated in a clinical controlled study.
A/C - should not be administered before the first estrus Do not administer to female pre -pubescent
Minipil
S/E – No (none ?)
A/C - Do not administer to diabetic females with uterine infection, immature,
pregnant or under estrogenic impregnation treatment.

Megedine
S/E - Increased appetite, weight gain, hyperplasia glandulocystic.
A/C - disorders of the reproductive tract and mammary tumors,diabetes, pregnancy,females. prepubescent  Do not use during pregnancy.
Use possible in case of lactation.

Opochaleurs
S/E - treatment can cause by prolonged repetitive administration and a
change of temperament, a development, breast increased
A/C - gestation appetite,Condition of the unit reproductive,female puberty, diabetes, breast tumors

Pilucalm
S/E - megestrol acetate causes in some cases an increase in appetite and weight gain.
These effects are transient and cease after shortly  stopping treatment.
A/C - acetate megestrol causes no pyometra or ovarian cyst. A bitch treated Pilucalm
20 may be normally fertilized his next heat with a normal pregnancy and
a normal range. Like all synthetic progestins, is against Pilucalm indicated in cases of
diabetes,uterine infection and pregnancy. Pilucalm 20 does will not be used if the female
is under estrogenic impregnation therapeutic

Pill'kan 5
S/E -treatment may lead to prolonged repetitive administration and a change of temperament, a development, breast  increased appetite
A/C Do not use if :
􀂃 genital disease,
�diabetes
􀂃breast tumors
􀂃 in pregnant females and females prepubescent


7
1.2. SUMMARY OF SIDE EFFECTS - CHAT
1.2.1.reported cases
Some MAHs laboratories, as shown in Table 4, the information collected before the
formal establishment of pharmacovigilance.
Table 4

Period covered by the periodic safety report
Date on the market
Distributed by ?
Period


Only cases reported since 1994 were considered. All adverse events following the use of these drugs to treat miliary dermatitis were excluded from this study. In response to the report, the names of eight veterinary drugs will anonymysé: Specialty-A,Specialty-B, Specialty-C,Specialty-D, Specialty-E,-Specialty-F, Specialty-G,Specialty-H
(abbreviation Sp on the graphs).

Ultimately, 70 cases reported in cats (Figure 1), including 16 fatal cases were evaluated. Such a statement can report adverse events to one or more animals, these to total
statements relate83 treated animals including 20 dead. For two veterinary drugs,
Specialty Specialty-C and Specialty -D, no cases have been reported.
Figure 1: Annual distribution of cases by specialty

Figure 1 Cases by brand name
Left column - Number of cases /Year
Bottom Row – year
Color coded by specialty (mfr name)


Figure 2 – Number of cases by brand name
58 of these cases involve adverse reactions in females, 9 cases involved
male animals and 3, no information is given on the sex of animals.
The number of reported cases was the most important for the specialty-B (48 cases). For other drugs,veterinary  the number of cases is lower: Specialty E-8, A-7,G-4,H- 2
F-1, C-0,D-0
.
I





Figure 3 Distribution of imputation for the reported adverse reactions following the administration of megestrol acetate in cats

In 70% of cases, the race of cats is unknown or unspecified. European breeds, Siamese,
Persian and chartreuse are respectively 22, 4, 3 and 1 of the owners identified.
The case description is often incomplete, and 55% of them (Figure 3), it was not possible to establish a link (imputation O) between the observed response and veterinary medicine based 'acetate megestrol-.
For 4 cases  Specialty E 3 cases and 1 Specialty A case - there is no link between the adverse effect and the drug symptomatology. for the rest of the synthesis, it was considered that these four cases "N" should be removed to determine the profile and  calculation of incidence. The remainder of the study focused on 66 cases charged A, B and O.






















1.2.3. Symptomatology
154 clinical signs were mentioned to describe 66 cases reported. It should be noted that several signs different clinical can be mentioned to describe each case. Figure 4 below and Table 5 show the relative proportion of these clinical signs.




Figure 4
Major clinical signs mentioned to describe the side effects in cats
(% sign / 154 clinical signs used to describe cases)

24% Major Functions
10% other ?
10% Nervous and behavioral
4% weight
5% Mucosa and skin
6% Sugar metabolism
3% fetal disorders
8% mammary tumor
5%  other disorders of the mammary gland
3% genital tract neoplasm
22% other genital disorders

Major Functions included all the effects on liver damage, kidney and gastrointestinal
Miscellaneous: General disorders + ineffective in 24% of reported cases of pyometra are diagnosed and represent approximately 42% (16/38) described in the lesions of the genital tract. Moreover, in about 20% of cases, tumors of the mammary gland are also notified. A single case of cancer of the mammary chain was reported by the owner without the diagnosis has been confirmed by a veterinarian. Pyometra and mammary tumors were associated only in two cases.


 

 
10
Table 5





Clinical signs mentioned in the case to describe the adverse reactions (case A-BO)
in cats

Number of times the sign is mentioned    **************  clinical signs   *  Number of times
reproductive tract tumor 4
tumor of ovaries or uterus4
Other diseases of the genital tract 34
            Pyometra16
            metritis, vaginal discharge uterine hypertrophy 18
tumor of mammary gland 13
tumor of mammary gland 12
breast carcinoma 1
Other disorders of the gland mammary 8
            hyperplasia mammary- 4
Swelling of the mammary gland abscess of the mammary gland mammary gland hypertrophy  - 4
Reproductive -4
Fetal Death mummification 4
Efficiency -5
Lack of efficacy- 5
Hyperglycemia carbohydrate10
Effect on metabolism 8
Hypoglycemia 2
Effect on skin and mucousa -7
congestion  cyanosis Alopecia Erythema Skin Dehydration 7
Effect on weight- 6
 weight gain, weight loss 6
Signs nervous and behavioral -16
Hyperesthesia  aggressiveness depression, apathy, lethargy,
ataxia, paresis 16
hyperthermia, hypothermia, prolapse of the third eyelid -7
Changing hematology: anemia, lymphocytosis, thrombocytopenia- 4
General disorders - 36
Kidney and bladder: renal failure, renal tumor,hematuria, urinary incontinence 5
Liver cirrhosis, jaundice, liver tumor 5
Lung dyspnea 3
Abdomen Abdominal Pain peritonitis, pancreatitis,7
Digestive tract: anorexia, polydipsia salivation, vomiting,constipation, diarrhea 16

Total 154 154
  • = Number of fatal cases not considered in this specification – 11
  •  
In 54% of reported cases, no information on the time to onset of adverse events from
the beginning of treatment is available. However, when we have the information, very large variations are observed in the timing of onset of pyometra or mammary tumors 2 days after the start of treatment in 10 years for the occurrence of pyometra and 15 days to 6 years for the appearance of a breast tumor.


 

1.2.4.incidence,

Arbitrarily  the incidence was calculated by taking as a basis the dosage regimen of one
tablet every 15 days to prevent heat. Thus, it has been estimated that the average cat
was likely to receive 24 tablets per year. Also were considered:
􀂃 average sales volume specialties over a year and specialty treated..
􀂃 the average number of cases per year for a specialty year
􀂃the number of animals likely to have been during one year





Table 6
Table 6 summarizes all the sales and calculate the incidence veterinary medicinal-.
Specialities

Calculation of incidence veterinary medicine (case A - B-O)  66 cases cat

Brand
Number pills sold
Number cases reported per year
Incidence per 100K pills
Number of animals treated
Incidence per 100K animals




 

Figures 5 and 6 provide a graphical illustration of the impact they are evaluated according to the number of animals treated or the number of tablets sold


Figure 5: Number of notifications reported sales figures (annual basis)

Figure 6: Number of notifications reported to the numbers of animals that have been treated
Number of animals treated (24 tablets per year)
Annual Incidence per 100K animals treated


13
For veterinary drugs also used for the treatment of miliary dermatitis, it was not
possible to estimate the proportion prescribed medications only under contraception. In
addition, for mixed veterinary drugs (for cats and dogs), it was not possible
to estimate the proportion of cats actually treated. It is noted that according to veterinary drugs, the incidence varies between 0 reactions and 4.1379 per 100,000 treated animals and between 0 and 0.1724 reactions 100,000 tablets sold.
In cats, the overall average incidence of reactions to 0.0645 100,000 tablets sold and
1.55 reactions per 100 000 animals receiving treatment 24 tablets per year, however, given the uncertainty calculations, these figures should be taken with caution.
February




 

14.STUDY OF SIDE EFFECTS REPORTED IN DOGS (did not copy charts)
2.1. DRUGS BASED MEGESTROL ACETATE FOR THE
PREVENTION AND INTERRUPTION OF HEAT
As for the cat, notices differ. Tables 7 and 8 show the veterinary medicinal  containing
productsmegestrol acetate available for the canine species and  treatment
recommendedregimens.
Table 7
Veterinary Drugsbased megestrol acetate available for the canine species
Drugs
Veterinary
content /
compressed package
Pilucalm 20 20 mg 16 tablets
10 mg 16 tablets Pilucalm
Pill'kan May 5 mg sugar8
Pill'kan20 20 8 sugarsmg
Canipil10 mg 20tablets
mg 10Minipil 5, 20 and 30
tablets
mgMegedine 10 16 and 32 tablets
Opochaleurs 10 mg 16 tablets or 8
Table 8
regimens of veterinary medicinal products containing megestrol acetate
in the canine species
Drugs
VeterinaryPrevention heat Interruption heat
Minipil 5 mg/10 kg / d 32 d before heat -
Pilucalm 20 5 mg/10 kg / day 32 days 20 mg/10 kg / day 8 days
Pilucalm 5 mg/10 kg / day 32 days 20 mg/10 kg / day 8 days (1)
Pill'kan May 5 mg/10 kg / j 32 days 20mg/10 kg / day 3 days then ½ dose
for 7 days (2)
Pill'kan May 20 mg/10 kg / day 32 days 20mg/10 kg / day 3 days then ½ dose
for 7 days
Canipil 5 mg / 10 kg / day 1 month 20 mg/10 kg / day 8 days
Opochaleurs 5 mg/10 kg / day 32 days
Megedine - 20 mg/10 kg / day 8 days
(1) other regimens for Pilucalm:
- lactation pseudopregnancy: 20 mg/10 kg / day for 8 days and 20 mg/10 kg, 2 times per week for 2
weeks
- hypersexuality 20 mg/10 kg / day for 7 days. If improved, continue at a dose of 10 mg/10 kg / day
for 14 days. If administered 40 mg/10 kg / day for 7 days and 10 mg/10 kg / day for 14 days. If
no improvement occurs, discontinue treatment-.
(2) other regimens for Pill'kan:
Hypersexuality in males: 20 mg/10 kg / day for 8 days, and 10 mg/10 kg / day for 8 days.
Table 9 shows the cons-indications and side / adverse effects brought on records
and / or on the label of veterinary medicinal products for dogs.
15
Table 9
Contraindications and side / adverse
side effects filed Name / adverse Contraindications and precautions
Minipil No
Do not administer to diabetic females
with uterine infection, immature, pregnant
or under estrogenic impregnation
treatment.
PILUCALM
megestrol acetate causes  some
incases, increased appetite and
decisionweight. These effects are transient and cease
shortly after discontinuation
of megestrol acetate does not cause
pyometra or ovarian cyst. A bitch
treated Pilucalm 20 may befertilized
normallyhis next heat with
a normal pregnancy and a normal range.
Like all synthetic progestogens,
Pilucalm is against-indicated in cases of
diabetes,uterine infection and pregnancy.
Pilucalm 20 will not be used if the female is
under estrogenic impregnationtherapeutic
PILL'KAN
treatment may exceptionally cause
by prolonged and repeated administration, a
change in temperament
mammary development,
increasedappetite
-.Affection of Reproductive
- Diabetes
- Female in gestation
- prepubescent females
-mammary tumors
CANIPIL Diabetes, pregnancy, metritis
Do not combine with estrogen hormones
OPOCHALEURS
Exceptionally, in case ofadministration:
prolonged and repetitive
behavior modification,development,
breast  increased of appetite
Diabetes, pregnancy,
prepubescent females,
reproductive condition of
mammary tumors
MEGEDINE Increased appetite, weight gain,
hyperplasia glandulocystic.
disorders of the reproductive tract andtumors,
mammary  diabetes, pregnancy, female
immature. Do not use during pregnancy-...
Can be used in case of lactation
16
2.2  SUMMARY OF SIDE EFFECTS - DOG
2.2.1. Number of reported cases
Some firms (Table 10) collected the information before the formal establishment of
pharmacovigilance.
Table 10
Period covered by the periodic safety report
Date of the
firm marketPeriod
Minipil11/02/1983 CEVA SANTE ANIMAL 1983 - 12/2002
20 Pilucalm
Pilucalm 24/02/1988 / 28/11/1983 NOVARTIS 1998-2002
Canipil VETO CENTRE 22/07/1987 01/01/1996 - 31/12/2002
Pill'Kan May 18 / 10/1985 CLEMENT - THEKAN 01/01/1999 - 31/12/2002
21/05/1984 Pill'Kan 20 CLEMENT - THEKAN 01/01/1999 - 31/12/2002
11/02/1983 Opochaleurs CLEMENT - 01 THEKAN / 01/1999 - 31/12/2002
Megedine ARKOMEDIKA 02/07/1980 01/01/1998 - 31/12/2002
For the remainder of this report on behalf of the seven veterinary drugs will anonymysé specialties: Specialty I,
J Specialty, Specialty-K-L Specialty, Specialty-M, N-Specialty, Specialty-O (Sp Abbreviation on
graphs.)
No adverse effects have been reported in dogs for veterinary medicinal Specialty K,
J Specialty, Specialty Specialty O and M. For other veterinary drugs, a total of 28 cases have been
reported (Figure 7): 20 cases Specialty I, 1 L Specialty cases, 7 cases Specialty N. Three of them were in
seriouscases resulting in death of the animal being treated. 30 dogs were treated.
Figure 7
Number of cases reported per year in the dog
0
1
2
3
4
5
6
7
Years
Case
sp L
SpI
SpN
94 95 96 97 98 99 00 01 02
17
2.2.2. Imputation
In this species, the description of the cases is sometimes incomplete, which has established only in
29% of reported cases, probable or possible relationship (imputation A or B) between the adverse event
and product administered ( Figure 8). However, it should be noted that in two cases reported for Specialty N
(7% of cases), it was clearly established that the observed effect was not related to the drug administered.
Figure 8
Distribution of imputation for reported adverse events following administration
of megestrol acetate in dogs
4%
25% 57%
7%
7%
A
B
O
N
Unassessable
2.2.3.symptoms
The two casescharged "N" have been removed to make the symptomatic profile, the study focused on the26
remainingcases (Figure 9). 57 clinical signs were noted (several clinical signs per case) to
describe the symptoms of these 26 cases as shown in Table 11.
Figure 9
Main clinical signs mentioned to describe the side effects in dogs
(% sign / number of clinical signs used for the description of cases)
14%
12%
19%
37%
2% 16%
of the mammary gland disorders
Disorders ofgenital
nervous signs and behavioral
efficiencyMissing:
Hematology and Biochemistry
Major Functions
Major Functions includes all effects for cardiac lesions, lung, liver, kidney and gastrointestinal
18
As shown in Table 11, only 4 cases of pyometra were diagnosed following the use product
oftheI and one case of breast hyperplasia. These pyometra occurred within 11 to 30
days after a few days of treatment (5-8 when information is available). In addition, several
reports (27% of cases) relate to complaints about the lack of efficacy (unwanted pregnancy,
pseudopregnancy, persistent unwanted heat or heat) of these veterinary drugs.
Table 11
Clinical signs mentioned in the case described adverse reactions (26 cases
AB-O)
Number of
times the
sign is
mentioned
clinical signs * Number of
times
Lack of efficacy Gestation unwanted, pseudopregnancy April
7Persistence of heat, heat unintended 3
4 Pyometra
disorders unit genital metritis 8 3
1 ovarian cyst
disorders of thegland
mammaryhyperplasia breast 1 1
nervous andsigns,
9behavioral
Aggression hyperarousal
weakness, apathy
sleepiness, tremors
agitation, depression
Tournis
9
Effect onparameters
haematological and
biochemical11
bleeding
réticulocytose
disorder bleeding
Anemia
leukocytosis,
elevated alanine transferase
High Cholesterol
11
Abdomen: distension 1
Liver: Jaundice 1
Heart: heart failure, tachycardia 2
Lungs: dyspnea, tachypnea 3
Kidney-Bladder: polyuria, hematuria, hemoglobinuria 5
Major Functions 21
digestive tract: anorexia, polyphagia, polydipsia,
salivation 9
* = number of fatal cases (3) not taken into account in this description
19
2.2.4. Incidence
Although several regimens are available and although the levels of active ingredient
different from a veterinarian to another drug, it was estimated that for treatment, the number of
tablets can vary between 8 and 32 depending on the veterinary drug . Forveterinary drugs
mixed(for cats and dogs), it was not possible to estimate the proportion of dogs actually
treatedABO.
Table 12
Calculation of the impact (annual average) Veterinary medicine
(26 cases  - DOG)
Specialty nonbre of
tablets
sold per year
number
Averageof
cases / year
Incidence /
100000comprimés
sold
Treatment
(*)
Number
animals
treated
Incidence /
100,000 Ax
Sp I 2 153 707 2.2222 0.1032 16 134 607 1.6509
Sp J 49 514 0.0000 0.0000 32 49 514 0.0000
Sp K 145 003 0.0000 0.0000 32 145 003 0.0000
Sp L 676 243 0.2000 0.0296 16 42 265 0.4732
Sp M 199 580 0.0000 0.0000 16 12 474 0.0000
Sp N 613 771 0.6250 0.1018 16 38 361 1.6293
sp.Ø 114 824 0.0000 0.0000 8 14 353 0.0000
Total 3952641 3.0472 0.0335-436 5760.5362
*= average number of tablets per treatment
Figures 10 and 11 provide a graphic illustration of the impact they are evaluated according
tothe number of animals treated or the number of tablets sold.
Figure 10: Number of notifications reported sales figures ( annual basis) in DOG
0
1  000000 000000 000000 000000 000
0002
3
4
5
0.0000
0.0200
0.0400
0.0600
0.0800
0.1000
0.1200
nonbre tablets sold 2153 49 514 145 003 676 243 199 580 613 771 114 824 3 952
Incidence/100 000cp sold 0.1032 0.0000 0.0000 0.0296 0.0000 0.1018 0.0000 0.0335
Sp I Sp Sp J K L Sp Sp Sp M N sp.ØTotal
20
Figure 11
number of notifications (annual average) compared to the number of animals which have been
treated (as recommended by 8, 16 or 32 tablets, according to veterinarian medicine)
0
50 000000000000000000000000000
100
000150
200
250
300
350
400
450
500
0.0000
0.2000
0.4000
0.6000
0.8000
1.0000
1.2000
1.4000
1.6000
1.8000
No. of animals treated 134 607 49 514 145 003 42 265 12 474 38 361 14 353 436 576
000 Incidence/100 Ax 1.6509 0.0000 0.0000 0.4732 0.0000 1 6293 0.0000 0.5362
Sp I Sp Sp J K L Sp Sp Sp M N Total sp.Ø
The average incidence of adverse effects in dogs was estimated at 0,536 reactions per 100 000animals.
treated  However, given the uncertainties regarding the actual number of tablets ingested during
treatmentand the inability to establish the proportion of dogs actually treated during treatment with
mixedspecialties (cat-dog), this figure must be treated with caution-..
21
3  LITERATURE DATA
3.1. LITERATURE DATA AT THE CAT
3.1. 1. Data on uterine
Endometrial hypertrophy due to megestrol acetate is proven in 10 cats previously ovariectomized receiving 10 to 30 mg of megestrol acetate per week (1). Lesions, except for a cat that declares a pyometra (lot 30 mg), partially regress after cessation of treatment. They exist also in non-ovariectomized cats (14)métropathies:.
A study has helped to identify the percentage of 1 case per 244 cats treated
for 3.5 years use.
(22) extended all progestin (15) can  cause pyometra and cystic hyperplasia and acetate
Megestrol is a relatively benign progestin. Other publications describe the effects on the uterus in the cat (26)
3.1. 2. Data on breast
In the feline species, megestrol acetate causes effects in the breast (17, 21) and of the
Hypertrophy breast. Authors (9 & 13) have established the link between non-neoplastic changes dominated by fibroadénomatose frequency and distribution of megestrol acetate. A survey very recent  MANAGED (study in breeding and canine sports group) led by Dr Martine Lennoz (unpublished results) showed that out of 53 cases of fibroadénomatose, 13 had received a treatment progestagen and that these blooms can breast occur following impregnation hormonal with normal doses of megestrol acetate. The appearance of mammary hyperplasia imposes a judgment of progestagen. Regression of lesions is often incomplete (18) suspected:.
The link between megestrol acetate and breast cancer has not been proven (3) but
First publication (10) reports that 3 out of 17 cancers of breast changes are due to
megestrol acetate and a second (25) reported that 17 cases of breast carcinoma, 4 were
developed on cats receiving progesterone.

3.1. 3. Other data
are the many publications on adverse effects described in the cat following
administration of megestrol acetate as hypoadrenocorticism (5, 6, 17), diabetes mellitus (17, 20),behavioral changes (aggression or depression, polyphagia) and weight gain (17, 21).It should be noted that publication (8) highlights the good tolerance to megestrol acetate.
22.
3.2  LITERATURE DATA IN DOGS (no edit)
3.2.1. Data on the uterus
In the bitch, progesterone also induces hyperplasia of the endometrium, pyometra (15) and
cystic hyperplasia (14). As in the cat, the number métropathies is low. Of 389 dogs
receiving megestrol acetate during proestrus (4), 0.8% said no and pyometra in
119 dogs treated for anoestrus.
3.2.2. Data on breast
In the bitch, repeated over a long period of progestin administration can lead to
breast hyperplasia, lactation and the onset of breast benign nodules (7, 19, 23, 24.)
In their study about 389 dogs receiving megestrol acetate during proestrus, Burke and
Reynolds (4) found that 5.9% of bitches have breast enlargement and 1% a
lactation.When megestrol acetate is distributed during anoestrus (119 dogs) the percentage
decrease (5% and 0.8%).
3.3. INFORMATION RIGHTS
The megestrol acetate for breast cancer-link process is not documented in the study except for MEGACE specialty produced by BRISTOL-MYERS SQUIBB is dosed at 160 mg of acetate megestrol and prescribed during the palliative treatment of carcinoma of the breast (antiestrogenic effect) in humans.This specialty is cons-indicated in pregnant women and / or have a history of thromboembolism.
A paragraph on pre-clinical safety of the summary of product characteristics indicates an
increase in the incidence of benign and malignant mammary tumors in dogs subjected
to megestrol acetate administration for seven years. Similar studies in rats and monkeys
have not demonstrated this phenomenon. The clinical relevance of these observations has not been established.
MEGACE for the study in the dog seems to attest to a sensitive species (dog) of the tissue breast to megestrol acetate.
CONCLUSIONS AND PROPOSALS
It should be noted that this study took into account cases that occurred before the establishment of veterinary pharmacovigilance operational since 2001 in France, to better define the nature of the adverse events following administration of these veterinary drugs. Since 2001, 33 cases cats and dogs have been reported including 32 charged A, B or O. As 37,758,167 tablets were sold during this period, the incidence of 0.088 per 100 000 tablets.
This study included 98 reports of adverse reactions in cats and dogs. They were
notified in 1994 and recorded December 31, 2002 for a total of 131,937,960 tablets
sold, which represents about 0,074 cases per 100,000 tablets sold. The incidence of reactions following administration of the oral progestin products based megestrol acetate seems so low.

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In addition, for six of these cases, it was concluded that the adverse event could not be linked to progestin ingested.
Notified side effects for 92 cases charged A, B or O (Table 13) are many and varied as
in cats than in dogs.
Table 13

Main clinical signs
Case (A, B, O)
                                        66 cases cat 26 cases dogs
Fatal                                                13                    3
Tumor of genital                                 4                   0
Pyometra                                         16                    4
Other disorders of the reproductive system (metritis, uterine hypertrophy ...)
                                                         18                    4
tumor of the mammary gland           13                    0
Other disorders of the breast              8                   1
Effect on sugar metabolism              10                   0
nervous and behavioral signs           16                   9


in cats are described:
- in approximately 54% of reported cases of diseases of the genital tract with particularly
métropathies
-in 20% of cases, non-cancerous tumors of the mammary gland, in this case,
literature data indicate firstly a breast hyperplasia megestrol acetate link
is established and secondly that the most common injury (fibroadénomatose) may occur at the beginning of treatment with megestrol acetate. All breast changes require a
judgment of non-recommended treatment in the instructions
-in 24% of cases, nerve and behavioral symptoms (aggression, depression, paresis ...)
with or without weight gain
-a few effects.the metabolism of sugar are also identified
in dogs are described:
- 30% of reported cases of diseases of the genital tract with particularly métropathies
-in less than 4% of cases, breast hyperplasia;
- in 35% of cases, nerve and behavioral symptoms (aggression, weakness, drowsiness,
restlessness ..)

The diversity of the wording of against-indications and side effects have been clearly identified. Most of the entries highlight the potential for use during pregnancy, uterine and breast disease, diabetes and association with estrogen. No one is suggesting the possibility of amétropathie after taking megestrol. Some entries even emphasize the absence of risk of pyometra. The possibility of breast modification is discussed. These changes are considered benign or reversible. The nature of this potentially tumor breast disease is never considered .Sometimes it is proposed to limit to 18 months duration of treatment to avoid adverse effects. Moreover, it is important to note that this study of identify the use of veterinary medicinal products based megestrol acetate in dermatology to treat feline "miliary dermatitis"(2, 16) can cause different side effects than observed when using as progestin  the fact the duration of treatment. An implementation of a study pharmacovigilance on megestrol acetate in the indication "miliary dermatitis" may be initiated-.at the end, as side effects may occur after the first dose of oral progestin, the terms "short and long-term "contained in the wording of the referral will not be included in the publication of the notice that will be on the side effects of progestin-only oral based Megestrol acetate used for the prevention and interruption of .heat in dogs and cats

- Given the relatively low incidence of adverse events reported less than
0.1per 100,000, the relevance of raising the exemption seems unfounded
-A  campaign information with retail distributors, pharmacists and veterinarians,
to raise awareness of the need to inform future users of the risks of adverse reactions may occur following the use of oral progestins to prevent or stop the heat in domestic carnivores, should be launched
-harmonization of labels and conditions should be considered and references
further to the adverse effects likely to be observed, must  included be on the outside label and, where appropriate, the instructions. The following wording on the side effects can be proposed: "After single or repeated administration, affections of the genital tract (hypertrophy, pyometra and uterine tumors) as well as conditions of the udder (hypertrophy and mammary tumors) were noted, cases of diabetes and behavioral changes (polyphagia, aggression or apathy) have also been reported
"-In addition, it would be:
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⇒ remind veterinarians and pharmacists their requirements for reporting
adverse effects occurred after the administration of these veterinary drugs
in domestic carnivores
⇒ further study by the MANAGED (study in reproduction, breeding and Group)
dog sport  and set up a prospective investigation of progestin based megestrol acetate, the protocol will be established by the pharmacovigilance centers.
26
REFERENCES
1. BELLENGER CR and JC CHEN effect of megestrol acetate on the endometrium of the prepubertally ovariectomised kitten Research in Veterinary Science 1990 * 48: 112-118
2. BOURDEAU P., BM PARAGON alternative to corticosteroids in dermatology Veterinary Rec. Med.vet168: 1992  645-660
3. BRETON C. FONTAINE JJ. Cases of cervical adenocarcinoma in a cat Vet Point 1990 22: 767-773
4. J. BURKE A. REYNOLDS Megestrol acetate for estrus postponement in the bitch JAVMA 1975 167: 307-309
5. CHASTAIN CB, CL et al GRAHAM Adrenocortical suppression in cats given megestro
Am.J.vet.Resacetate.1981 42: 2029-2035
6. CHURCH DB et al Effects of proligestone and megestrol on plasma adrenocorticotrophic hormone, insulin and insulin-like growth factor-1 concentrations in cats Res Vet Sci 1994 56: 175-8
7. DONNAY I., ravished J., J. VERSTEGEN Influence of hormonal background on the clinical appearance of mammary tumors in dogs Ann. Med. Vet. 1994 138: 109-117
8. Feldman EC, Nelson RW Feline Reproduction in Canine and Feline Endocrinology and reproduction WB Saunders, Philadelphia 1996:759-756
9. HAYDEN DW et al. Feline mammary hypertrophy / fibroadenoma complex: clinical and hormonal aspects Am J Vet Res 1981 42: 1699-1703
10. HAYDEN DW BARNES DM et al Morphologic exchange in the mammary gland of megestrol acetate treated and untreated cats: a retrospective study. Vet pathol 26 1989 26: 104-113
11. Henik RA, OLSON PN ROSYCHUCK, RA Progestagen therapy in cats Compend. Contin. Educ. Pract. 7 1985: 132-138
12. HERRTAGE ME et al Diabetic retinopathy in a cat with megestrol acetate-induced diabetes J.smal Anim. Pract. 1985 26: 595-601
13. HINTON GASKELL Mr CJ Non-neoplasic mammary hypertrophy in the cat associated with either pregnancy or with oral progestagen therapy Vet. Rec. 1977 100: 277-280
14. HOLST BS et al Uterine pathology in cats routinely ovariohysterectomised Proccedings EVSSAR 3rd European Congress Liege May 2002
15 .JOHNSON CA Uterine disease in Textbook of Veterinary Internal Medicine of the dog and cat ETTINGER SJ 3rd Edition, 1989: 1797-1805 27
16. KUNKLE GA Progestgens in dermatology in Current Veterinary Therapy, RW Kirk, 9th Ed, WB Saunders, Philadelphia, 1986, 601-605
17. Lennoz (M) Medical contraception Proceeding National Congress CNVSPA November 2000.
18. Lennoz (M) et al. Special features of the pathology of feline reproduction Prat. Med. Anim. Comp34.1999  449-462
19. NELSON LW and al Canine Mammary neoplasms and progestogens abbreviation différente JAMA *1972 219: 1601-1606
20. PETERSON ME Effects of megestrol acetate on glucose tolerance and growth hormone secretion in the cat  Res Vet Sci 1987 42: 354-357
21. ROMATOWSKI J. Use of megestrol acetate JAVMA 1989 194: 700-702
22. OEEN EO: The oral administration of megestrol acetate to postpone oestrus in cats, Nordisk Veternaermedicin, 1977, 29: 287-291
23. Selman PJ et al Progestin treatment in dogs Eur. J. Endocrinol. 1994 131: 413-421
24. Selman PJ et al Progestin-induced GH excess in the dog originates in the mammary gland Eur. J.Endocrinol. 1994 134: 287-292
25. TOMLINSON MJ et al feline mammary carcinoma: a retrospective assessment of 17 cases Can Vet J
1984 25: 435-439
26. WALKER EC Oral progestagens in cats Vet. Rec. 1975 96 458
Other items consulted but not cited:
CONCANNON PW, VN MEYERS-WALLEN Current and Proposed methods for contraception and termination of pregnancy in dogs and cats JAVMA 1991; 198:1214-1225
JOHNSON SD, ROOT KUSTRITZ MV OLSON PNS Disorders of the feline uterus and uterine tubes (oviducts) in Canine and Feline Theriogenology 2001 WB Saunders, Philadelphia: 463-471


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